The primary purpose of the current proposal is to investigate the ability of Yohimbine Hydrochloride to induce a rapid relief of depression in combination with the classical antidepressant agent, desipramine (DMI). This new treatment approach is based upon studies in laboratory rats which demonstrated that long term administration of a variety of structurally and biochemically dissimilar antidepressant agents decrease the sensitivity and density of brain beta adrenergic receptors, suggesting that this effect is critical to the development of antidepressant activity. Several recent animal investigations have observed that when yohimbine is administered in combination with DMI, the decrease in beta receptors occurs with 4 days instead of the 4 to 6 weeks required when DMI is given alone. In the current proposal severely depressed inpatients will be treated in a double blind placebo controlled study with either DMI or a DMI-yohimbine combination. Patients will be rated twice daily using a short clinical rating scale and three times weekly with the Hamilton Depression Scale to determine if the yohimbine-DMI combination induces a more rapid relief of depression than DMI alone. To examine the relationship between change in clinical state and norepinephrine (NE) turnover, twenty-four hour urinary MHPG and plasma free MHPG levels will be determined three times weekly. A second purpose of this proposal is to use the effect of yohimbine on NE turnover to assess alpha-2 adrenergic receptor sensitivity in depressed patients. Yohimbine increases brain NE turnover by selectively blocking the inhibitory presynaptic alpha-2 adrenergic receptor. It has been hypothesized that alpha-2 adrenergic receptor sensitivity is increased in depression resulting in decreased NE turnover and that the mechanism of action of some antidepressants is to decrease the sensitivity of the alpha-2 adrenergic receptor. The current proposal will test these hypotheses by comparing the effect of yohimbine on plasma free MHPG in healthy control subjects and drug free depressed patients and by determining the effect of DMI treatment on the plasma free MHPG response to yohimbine. Additionally, the relationship among clinical response, the pretreatment plasma MHPG responses to yohimbine, and the effect of antidepressant treatment on the plasma MHPG response to yohimbine will be studied.